n-Docosanol is a 22-carbon primary alcohol that can inhibit herpes simplex virus (HSV) replication in tissue culture and cutaneous HSV disease in guinea pigs. Recent clinical trials documented that a cream formulation of n-docosanol is safe and effective for the treatment of herpes labialis in humans, and a New Drug application has been submitted to the Food and Drug Administration for marketing approval for the indication. The guanosine analog acyclovir remains a leading approved drug for the treatment of oral and genital HSV diseases. Clinical data indicate that antiviral therapy for such diseases can still be substantially improved over what is observed with acyclovir or n-docosanol monotherapy. Combination therapy using drugs with disparate mechanisms of action has proven to be highly effective for the treatment of viral diseases. Combination therapy with n-docosanol plus acyclovir would be reasonable because a) they have distinctly different mechanisms of action for inhibition of HSV replication, b) both exhibit favorable toxicity profiles, and c) it was recently observed that n-docosanol can synergistically enhance the anti-HSV activity of acyclovir in tissue culture. The purpose of this proposed research is to corroborate these tissue culture results using a cutaneous HSV model in guinea pigs. Skin on the backs of guinea pigs will be inoculated with HSV. The skin sites will be treated with n-docosanol and acyclovir, alone or in combination. If combination therapy using n-docosanol plus acyclovir proves to be substantially better than either drug alone in the model, feasibility would be indicated for this strategy in the treatment of primary and recurrent mucocutaneous HSV disease in humans. PROPOSED COMMERCIAL APPLICATION: Less than 1 in 5 US patients with recurrent HSV disease seek treatment, in part, because presently approved drugs limit the disease from a duration of approximately 6 days to approximately 5 days. If a combination of n- docosanol plus acyclovir can be shown to have clear benefits over either drug alone, a substantial marketing advantage would be indicated. This is particularly true if an effective combination can be delivered as a topical formulation, emphasis of this research.